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【结 构 式】 
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【分子编号】29906 【品名】ethyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate 【CA登记号】 |
【 分 子 式 】C16H26N4O4 【 分 子 量 】338.407 【元素组成】C 56.79% H 7.74% N 16.56% O 18.91% |
合成路线1
该中间体在本合成路线中的序号：(XIIII)1) The reaction of (-)-quinic acid (I) with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid in refluxing acetone gives the protected lactone (III), which by treatment with sodium ethoxide in ethanol yields the ethyl ester (IV). The acylation of (IV) with mesyl chloride and TEA in dichloromethane affords the mesylate (V), which is dehydrated with SO2Cl2 in dichloromethane, giving the cyclohexenecarboxylate (VI). The transketalization of (VI) with 3-pentanone and HClO4 affords the 3,4-pentylidene ketal (VII), which is cleaved with borane methyl sulfide complex to the 3-pentyl ether (VIII). The epoxidation of (VIII) by treatment with KHCO3 in hot ethanol affords the epoxide (IX), which is opened with sodium azide and ammonium chloride in ethanol/water, resulting in the the azido alcohol (X). The cyclization of (X) with triphenylphosphine in refluxing THF/acetonitrile or trimethylphosphine in anhydrous acetonitrile yields aziridine (XI), which is opened by means of sodium azide in hot DMF to the azidoamine (XII). The acetylation of (XII) with acetic anhydride provides the azidoacetamide (XIII), which is reduced with H2 over Lindlar catalyst or over RaNi in ethanol and treated with 85% phosphoric acid.
| 【1】 Rohloff, J.C.; Kent, K.M.; Postich, M.J.; et al.; Practical total synthesis of the anti-influenza drug GS-4104. J Org Chem 1998, 63, 13, 4545. |
| 【2】 Castañer, J.; Leeson, P.A.; Graul, A.; Oseltamivir Phosphate. Drugs Fut 1999, 24, 11, 1189. |
| 【3】 McGee, L.R.; Kent, K.M.; Portich, M.J.; Kim, C.U.; Williams, M.A.; Zhang, L.; Prisbe, E.J.; Rohloff, J.C.; Munger, J.D.; St. John, D.E. (Gilead Sciences Inc.); Preparation of cyclohexene carboxylate derivs.. WO 9807685 . |
| 【4】 Postich, M.J.; Williams, M.A.; Rohloff, J.C.; Prisbe, E.J.; McGee, L.R.; Kent, K.M.; Munger, J.D.; Zhang, L.; Kim, C.U.; Kelly, D.E. (Gilead Sciences Inc.); Preparation of carbocyclic cpds.. US 5886213 . |
| 【5】 Bischofberger, N.W.; Kim, C.U.; Williams, M.A.; Mills, R.G.; Hitchcock, M.J.M.; Dahl, T.C.; Lew, W.; Liu, H. (Gilead Sciences Inc.); Cpds. containing six-membered rings, processes for their preparation, and their use as medicaments. EP 1015417; WO 9914185 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIII) | 29906 | ethyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C16H26N4O4 | 详情 | 详情 | |
| (I) | 11524 | D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid | 77-95-2 | C7H12O6 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 29896 | (1R,2R,6R,8S)-8-hydroxy-4,4-dimethyl-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undecan-9-one | C10H14O5 | 详情 | 详情 | |
| (IV) | 29897 | ethyl (3aR,5R,7R,7aS)-5,7-dihydroxy-2,2-dimethylhexahydro-1,3-benzodioxole-5-carboxylate | C12H20O6 | 详情 | 详情 | |
| (V) | 29898 | ethyl (3aR,5S,7R,7aR)-5-hydroxy-2,2-dimethyl-7-[(methylsulfonyl)oxy]hexahydro-1,3-benzodioxole-5-carboxylate | C13H22O8S | 详情 | 详情 | |
| (VI) | 29899 | ethyl (3aR,7R,7aR)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C13H20O7S | 详情 | 详情 | |
| (VII) | 29900 | ethyl (3aR,7R,7aR)-2,2-diethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C15H24O7S | 详情 | 详情 | |
| (VIII) | 29901 | ethyl (3R,4R,5R)-3-(1-ethylpropoxy)-4-hydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C15H26O7S | 详情 | 详情 | |
| (IX) | 29902 | ethyl (1S,5R,6S)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C14H22O4 | 详情 | 详情 | |
| (X) | 29903 | ethyl (3R,4S,5R)-5-azido-3-(1-ethylpropoxy)-4-hydroxy-1-cyclohexene-1-carboxylate | C14H23N3O4 | 详情 | 详情 | |
| (XI) | 29904 | ethyl (1R,5R,6R)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C14H23NO3 | 详情 | 详情 | |
| (XII) | 29905 | ethyl (3R,4R,5S)-4-amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C14H24N4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)2) The esterification of Shikimic acid (XIV) with MeOH/TsOH gives the methyl ester (XV), which is treated with 2,2-dimethoxypropane (II) and TsOH to yield the acetonide (XVI). The mesylation of (XVI) with mesyl chloride and TEA in dichloromethane gives the mesylated acetonide (XVII), which is hydrolyzed with HCl, yielding the dihydroxy ester (XVIII). The epoxidation of (XVIII) with DBU in THF affords the epoxide (XIX), which is protected with methyl chloromethyl ether to give compound (XX). The reaction of (XX) with sodium azide in refluxing methanol/water provides the hydroxy azide (XXI), which is acylated with mesyl chloride to the mesylate (XXII). The cyclization of (XXII) by means of triphenylphosphine in THF affords the aziridine (XXIII), which is treated with sodium azide in hot DMF to give the amino azide (XXIV). The deprotection of (XXIV) with HCl followed by tritylation of the free amino group with trityl chloride and TEA yields compound (XXV), which is cyclized by means of mesyl chloride and TEA to afford the tritylaziridine (XXVI). The cleavage of the aziridine ring of (XXVI) with 3-pentanol, followed by acetylation of the resulting amino group, affords the acetamido aziridine (XXVII), which is hydrolyzed at the ester group with KOH in THF/water to give the carboxylic acid (XXVIII). The esterification of (XXVIII) with ethanol, DCC and DMAP in dichloromethane affords the azido ester (XIII), which is finally reduced with triphenylphosphine in hot THF/water.
| 【1】 Castañer, J.; Leeson, P.A.; Graul, A.; Oseltamivir Phosphate. Drugs Fut 1999, 24, 11, 1189. |
| 【2】 Bischofberger, N.W.; Kim, C.U.; Lew, W.; Liu, H.; Williams, M.A. (Gilead Sciences Inc.); Novel selective inhibitors of viral or bacterial neuraminidases. EP 0759917; EP 0976734; JP 1999501908; WO 9626933 . |
| 【3】 Bischofberger, N.W.; Kim, C.U.; Williams, M.A.; Lew, W.; Liu, H. (Gilead Sciences Inc.); Carbocyclic cpds.. US 5763483 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 | |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XIII) | 29906 | ethyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C16H26N4O4 | 详情 | 详情 | |
| (XIV) | 29907 | (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid; Shikimic acid | 138-59-0 | C7H10O5 | 详情 | 详情 |
| (XV) | 29908 | methyl (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate | C8H12O5 | 详情 | 详情 | |
| (XVI) | 29909 | methyl (3aR,7R,7aS)-7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C11H16O5 | 详情 | 详情 | |
| (XVII) | 29910 | methyl (3aR,7R,7aR)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C12H18O7S | 详情 | 详情 | |
| (XVIII) | 29911 | methyl (3R,4R,5R)-3,4-dihydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C9H14O7S | 详情 | 详情 | |
| (XIX) | 29912 | methyl (1S,5R,6R)-5-hydroxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C8H10O4 | 详情 | 详情 | |
| (XX) | 29913 | methyl (1S,5R,6S)-5-(methoxymethoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H14O5 | 详情 | 详情 | |
| (XXI) | 29914 | methyl (3R,4S,5R)-5-azido-4-hydroxy-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H15N3O5 | 详情 | 详情 | |
| (XXII) | 29915 | methyl (3R,4S,5R)-5-azido-3-(methoxymethoxy)-4-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C11H17N3O7S | 详情 | 详情 | |
| (XXIII) | 29916 | methyl (1R,5R,6R)-5-(methoxymethoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H15NO4 | 详情 | 详情 | |
| (XXIV) | 29917 | methyl (3R,4R,5S)-4-amino-5-azido-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H16N4O4 | 详情 | 详情 | |
| (XXV) | 29918 | methyl (3R,4R,5S)-5-azido-3-hydroxy-4-(tritylamino)-1-cyclohexene-1-carboxylate | C27H26N4O3 | 详情 | 详情 | |
| (XXVI) | 29919 | methyl (1S,5S,6S)-5-azido-7-trityl-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate | C27H24N4O2 | 详情 | 详情 | |
| (XXVII) | 29920 | methyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C15H24N4O4 | 详情 | 详情 | |
| (XXVIII) | 29921 | (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid | C14H22N4O4 | 详情 | 详情 |